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Background   Bacillus anthracis  is the etiological agent of anthrax. Lethal toxin (LT) produced by  B. anthracis  is a well-known key virulence factor for anthrax because of its strong cytotoxic activity. However, little is known about the role of  B. anthracis  genomic DNA (BAG) in anthrax pathogenesis.    Results  We examined the effect of BAG on TNF-α production and LT-mediated cytotoxicity during  B. anthracis  spore infection in mouse macrophage cell lines (RAW264.7 cells and J774A.1) and BALB/c mice. Infection of RAW264.7 cells with  B. anthracis  spores induced TNF-α expression in a multiplicity of infection (MOI)-dependent manner, and this enhancement was attenuated by the toll-like receptor (TLR) 9 inhibitor oligodeoxynucleotide (ODN)2088. BAG led to TNF-α expression in a dose- and time-dependent manner when applied to RAW264.7 cells. TNF-α expression induced by BAG was reduced by either pretreatment with TLR9 inhibitors (ODN2088 and chloroquine (CQ)) or transfection with TLR9 siRNA. Furthermore, BAG-induced TNF-α production in TLR9 +/+  macrophages was completely abrogated in TLR9 −/−  macrophages. BAG enhanced the phosphorylation of mitogen-activated protein kinases (MAPK), and BAG-induced TNF-α expression was attenuated by pretreatment with MAPK inhibitors. A reporter gene assay and confocal microscopy demonstrated that BAG increased NF-κB activation, which is responsible for TNF-α expression. Treatment with BAG alone showed no cytotoxic activity on the macrophage cell line J774A.1, whereas LT-mediated cytotoxicity was enhanced by treatment with BAG or TNF-α. Enhanced LT-induced lethality was also confirmed by BAG administration in mice. Furthermore, LT plus BAG-mediated lethality was significantly recovered by administration of Infliximab, an anti-TNF-α monoclonal antibody.    Conclusions  Our results suggest that  B. anthracis  DNA may contribute to anthrax pathogenesis by enhancing LT activity via TLR9-mediated TNF-α production.    Electronic supplementary material  The online version of this article (doi:10.1186/s12866-014-0300-9) contains supplementary material, which is available to authorized users.

Bacillus anthracis genomic DNA enhances lethal toxin–induced cytotoxicity through TNF-α production